Enzymes categorized under the rubric of "DNA topoisomerase" control the topology of DNA over the course of conformational and topological changes which occur during many cellular processes. For example, DNA topoisomerases are involved in DNA replication, RNA transcription and recombination.
Two kinds of DNA topoisomerases are recognized generally. Type I and type II enzymes catalyze topological changes in DNA by transiently breaking one strand or two strands of the DNA helix, respectively. The relaxation of superhelical DNA is a characteristic reaction catalyzed by a topoisomerase I ("top 1"), while a topoisomerase II ("top 2") catalyzes the passing of two DNA segments in a manner leading to such topoisomerization reactions of DNA as supercoiling/relaxation, knotting/unknotting and catenation/decantenation.
DNA topoisomerase II has been implicated as the chemotherapeutic target for a diverse group of antitumor agents, including epipodophyllotoxins, anthracyclines, acridines, anthracenediones and ellipticines. See Macdonald et al., in DNA TOPOISOMERASES IN CANCER 199-214 (Oxford University Press 1991) (hereafter "Macdonald (1991)"), the contents of which are hereby incorporated by reference. Under the influence of such drugs, top 2 is believed to cleave DNA and form a concomitant covalent association with the broken strand(s) of duplex DNA. The formation of such "cleavable complexes" of drug, DNA and top 2 enzyme has been attributed to the stabilization by the drug of a covalent, DNA-bound catalytic intermediate in the cleavage-resealing sequence of the enzyme. Id.
New inhibitors of top 2 have been identified after they were noted for their antitumor properties. Some, such as amonafide, genistein and the terpenoides, act in the manner of the above-mentioned drugs, by trapping cleavable complexes. Antitumor compounds like merbarone and fostriecin, by contrast, inhibit top 2 activity without stabilizing cleavable complexes.
While attempting to elucidate mechanistic issues in this field, including the nature of binding site(s) for top 2 inhibitors in the ternary complex, Macdonald (1991) formulated a composite model by superimposing structural subunits of top 2 inhibitors from the five classes of compounds mentioned previously, namely, epipodophyllotoxins, anthracyclines, acridines, anthracenediones and ellipticines. The composite, three-domain pharmacophore encompassed, inter alia, a family of hybrid structures which incorporated, respectively, substructural elements from each class of top 2 inhibitors. The "unified pharmacophore" model was not refined sufficiently, however, to allow for a priori predictions of any certainty regarding the activity, if any, of actual molecules deemed within the ambit of the composite.